O-6-Alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein which corrects promutagenic O-6-methylguanine lesions in DNA by removing the alkyl group from the guanyl moiety. In this reaction, the alkyl group is transferred to a cysteine residue in the active site of AGT, inactivating it. Elevated activity of AGT is responsible for resistance of tumor cells to cancer chemotherapies involving DNA alkylation such as chloroethylnitrosoureas (CENUs). Therefore, inactivation of AGT effectively potentiates current alkylation chemotherapies. One AGT inhibitor, o-6-benzylguanine, is currently in phase II studies as such a potentiation therapy. To begin a program of structure-based drug design using AGT, the inhibitors O-6-benyzlguanine (BG) and O-6-(3-iodobenzyl)guanine (IBG) were synthesized. AGT was cocrystallized with BG and IBG. Diffraction data from the AGT-BG complex was collected to 2.3 E at a synchotron source. Currently, heavy metal derivatives of the complex are being pursued. The structure of the AGT-BG complex will then be used to improve existing inhibitors and generate novel ones by complementation to the active site.